The present invention relates to novel prostaglandin I.sub.2 derivatives, more particularly, to 5,6,7-trinor-4,8-inter-m-phenylene prostaglandin I.sub.2 derivatives.
Prostaglandin I.sub.2, hereinafter referred to as PGI.sub.2, of the formula ##STR2## was first found by J. R. Vane et. al. in 1976 and is biosynthesized from arachidonic acid via endoperoxide(PGH.sub.2 or PGG.sub.2) in the vascular wall. PGI.sub.2 is well known to show potent activity to inhibit platelet aggregation and to dilate peripheral blood vessels (C & EN, Dec. 20, 1976, page 17 and S. Moncade et al., Nature, 263,633(1976)).
Because of the unstable exo-enolether structure thereof, PGI.sub.2 is extremely unstable even in a neutral aqueous solution and is readily converted to 6-oxo-PGF.sub.1.alpha. which is almost physiologically inactive. Such instability of PGI.sub.2 is a big obstacle to its use as a drug. Furthermore, PGI.sub.2 is unstable in vivo as well and shows only short duration of action.
The compounds of the present invention are novel PGI.sub.2 derivatives in which the exo-enolether moiety characteristic of PGI.sub.2 is transformed into "inter-m-phenylene" moiety. In this sense the compounds may be regarded as analogs of PGI.sub.2.
The compounds of the present invention feature much improved stability in vitro as well as in vivo in comparison with PGI.sub.2. The compounds are highly stable even in an aqueous solution and show long duration of action in vivo. Further, the compounds have advantages over PGI.sub.2 for pharmaceutical application because they exhibit more selective physiological actions than PGI.sub.2, which has multifarious, inseperable biological activities.
Some prostaglandin I.sub.2 derivatives which have 5,6,7-trinor-4,8-inter-m-phenylene structure have already been described in publication by some of the present authors. (Kiyotaka Ohno, Hisao Nishiyama and Shintaro Nishio, U.S. Pat. No. 4,301,164 (1981)). But, the compounds of the present invention, which feature the presence of alkynyl side chain, have more potent physiological activities as well as decreased side effects than the already disclosed compounds analogous to those of the present invention.
It is an object of this invention to provide novel prostaglandin I.sub.2 derivatives which are stable and possess platelet aggregation-inhibiting, hypotensive, anti-ulcer and other activities.
Another object of this invention is to provide the compounds improved on physiological efficacy as compared with the compounds which have already been disclosed by some of the present authors.
Other objects and advantages of this invention will be apparent from the description hereinbelow.